Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia: a systematic review with individual patient data network meta-analysis

Veroniki, Areti Angeliki, Ashoor, Huda M, Rios, Patricia, Seitidis, Georgios, Stewart, Lesley, Clarke, Mike, Tudur-Smith, Catrin ORCID: 0000-0003-3051-1445, Mavridis, Dimitris, Hemmelgarn, Brenda R, Holroyd-Leduc, Jayna
et al (show 2 more authors) (2022) Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia: a systematic review with individual patient data network meta-analysis. BMJ OPEN, 12 (4). e053012-.

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<h4>Objective</h4>To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD).<h4>Design</h4>Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.<h4>Data sources</h4>MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.<h4>Participants</h4>80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.<h4>Interventions</h4>Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.<h4>Data extraction and synthesis</h4>We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).<h4>Primary and secondary outcomes</h4>We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.<h4>Results</h4>Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.<h4>Conclusions</h4>The choice among the different cognitive enhancers may depend on patient's characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.<h4>Prospero registration number</h4>CRD42015023507.

Item Type: Article
Uncontrolled Keywords: dementia, epidemiology, statistics & research methods
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Population Health
Depositing User: Symplectic Admin
Date Deposited: 07 Sep 2022 09:10
Last Modified: 18 Jan 2023 20:45
DOI: 10.1136/bmjopen-2021-053012
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